Download 3-Hour Bundle - Surviving Sepsis Campaign

3-Hour Bundle
1. Measure Lactate Level
Background
Hyperlactatemia is typically present in patients with severe sepsis or septic shock and may
be secondary to anaerobic metabolism due to hypoperfusion or other complex factors. The
prognostic value of raised blood lactate levels has been well established in septic shock
patients[1], particularly if the high levels persist.[2,3] In addition, blood lactate levels have
been shown to have greater prognostic value than oxygen-derived variables.[4] Obtaining
a lactate level is essential to identifying tissue hypoperfusion in patients who are not yet
hypotensive but who are at risk for septic shock.
Limitations
The interpretation of blood lactate levels in septic patients is not always straightforward.
A number of studies have suggested that elevated lactate levels may result from cellular
metabolic failure in sepsis rather than from global hypoperfusion. Elevated lactate levels can
also result from decreased clearance by the liver. Although blood lactate concentration may
lack precision as a measure of tissue metabolic status, elevated levels in sepsis support
aggressive resuscitation.
Implications
Given the high risk for septic shock, all patients with elevated lactate >4 mmol/L (36 mg/dL)
enter the early goal-directed therapy portion of the 6-Hour Septic Shock Bundle, regardless of
blood pressure. Mortality is high in septic patients with both hypotension and lactate ≥4 mmol/L
(46.1 percent). Mortality is also increased in severely septic patients with hypotension alone
(36.7 percent) and lactate ≥4 mmol/L alone (30 percent).[5] This approach is consistent with
the trial that established the value of early goal-directed therapies.[6]
Turnaround Time
Lactate levels must be available in your institution with rapid turnaround time (within minutes)
to effectively treat severely septic patients. An arterial blood gas analyzer located in the
clinical laboratories usually satisfies this requirement. However, any means of rapid turnaround
time is acceptable. In some cases, it will be essential for hospitals to invest in adequate
equipment in order to meet present standards of care for septic patients.
The technique of obtaining lactate by venipuncture typically carries a 24- to 48-hour turnaround
time and will not be suitable to care for septic patients. This technique also requires special
collection conditions, such as without the use of tourniquet, which will likely hinder proper
clinical care.
3-Hour Bundle
Arterial vs. Venous Lactate
The question has been raised several times as to whether an arterial or venous lactate
sample is required. While there is no consensus of settled literature on this question, an
elevated lactate of any variety is typically abnormal and must be explained. Either collection is
appropriate for bundle compliance. Lactate elevations may be influenced by other conditions
such as a variety of medications, hepatic insufficiency, or hyperlactatemia due to primarily
cardiac causes of hypoperfusion.
Grading the Evidence
■
he use of lactate as a method to detect severe sepsis and septic shock and as a
T
rationale for further therapies was evaluated as part of the larger recommendation on initial
resuscitation in the 2012 Surviving Sepsis Campaign Guidelines. There, the guidelines
committee recommended the protocolized, quantitative resuscitation of a patient with
sepsis-induced shock, defined as tissue hypoperfusion (hypotension persisting after initial
fluid challenge or blood lactate concentration equal to or greater than 4 mmol/L).
Evidence Grade 1C: This is a strong recommendation for care based on a number of
qualitative considerations. “C” level evidence generally derives from randomized control trials
with certain limitations or very well-done observational or cohort studies.
■
he strategy of clearing lactate to normal values was also assessed in the 2012 Surviving
T
Sepsis Campaign Guidelines. The Campaign suggests targeting resuscitation to normalize
lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion.
Evidence Grade 2C: This is a suggestion for care based on a number of qualitative
considerations. “C” level evidence generally derives from randomized control trials with certain
limitations or very well-done observational or cohort studies [7].
References
1. W
eil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute
circulatory failure (shock). Circulation. 1970;41:989-1001.
2. Vincent JL, Dufaye P, Berre J, et al. Serial lactate determinations during circulatory shock. Critical Care Medicine.
1983;11:449-451.
3. Friedman G, Berlot G, Kahn RJ, et al. Combined measurements of blood lactate concentrations and gastric
intramucosal pH in patients with severe sepsis. Critical Care Medicine. 1995;23:1184-1193.
4. Bakker J, Coffernils M, Leon M, et al. Blood lactate levels are superior to oxygen derived variables in predicting
outcome in human septic shock. Chest. 1991;99:956-962.
5. Focht A, Jones AE, Lowe TJ. Early goal-directed therapy: improving mortality and morbidity of sepsis in the
emergency department. Jt Comm J Qual Patient Saf. 2009;35:186-91.
6. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic
shock. New England Journal of Medicine. 2001;345:1368-1377.
7. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early
sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-746.
Content adapted extensively from:
■ Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: An evidence-based review. Critical
Care Medicine. 2004;32(11):(Suppl.)S451-S454.
■ Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of
severe sepsis and septic shock: 2012. Critical Care Medicine. 2013 Feb;41(2):580-637.
3-Hour Bundle
TIPS
1. If serum lactate is not rapidly available in your institution, invest in equipment to make
rapid assessment possible. This should be presented to hospital and laboratory
administration as a present standard of care.
2. C
reate a standardized protocol to manage severe sepsis that includes measurement
of lactate.
3. Include a prompt on arterial blood gas requisitions or physician order entry to prompt
users to order lactate for suspected severe sepsis.
3-Hour Bundle
2. O
btain Blood Cultures Prior to
Administration of Antibiotics
Related Measures
Timing of Blood Cultures
Background
The incidence of sepsis and bacteremia in critically ill patients has been increasing in the past
two decades.[8,9] Thirty percent to 50 percent of patients presenting with a clinical syndrome
of severe sepsis or shock have positive blood cultures. Therefore, blood should be obtained
for culture in any critically ill septic patient.
Collecting blood cultures prior to antibiotic administration offers the best hope of identifying
the organism that caused severe sepsis in an individual patient. Failure to check blood cultures
prior to antibiotic infusion will perhaps affect the growth of any blood borne bacteria and
prevent a culture from becoming positive later.
Collection Strategy
Two or more blood cultures are recommended with at least one drawn percutaneously
and one drawn through each vascular access device, unless the device was recently
inserted (<48 hours).[1,2] In patients with suspected catheter-related infection, a pair of
blood cultures obtained through the catheter hub and a peripheral site should be obtained
simultaneously. Cultures of other sites (preferably quantitative, where appropriate), such as
urine, cerebrospinal fluid, wounds, respiratory secretions, or other body fluids that may be
the source of infection should also be obtained before antimicrobial therapy.[2] If the same
organism is recovered from both cultures, the likelihood that the organism is causing the
severe sepsis is enhanced. In addition, if the culture drawn through the vascular access device
is positive much earlier than the peripheral blood culture (i.e., >2 hours earlier), it may offer
support that the vascular access device is the source of the infection.[3] Volume of blood may
also be important.[4]
3-Hour Bundle
Indications
Fever, chills, hypothermia, leukocytosis, left shift of neutrophils, neutropenia, and the
development of otherwise unexplained organ dysfunction (e.g., renal failure or signs of
hemodynamic compromise) are specific indications for obtaining blood for culture. Blood
cultures should be taken as soon as possible after the onset of fever or chills.
While it remains difficult to predict bacteremia in patients with sepsis[5], a number of clinical
and laboratory parameters are independently correlated with the presence of bacteria in the
blood of patients when infection is suspected. These include chills, hypoalbuminemia, the
development of renal failure, and a diagnosis of urinary tract infection[5,6]; other criteria are
new fever, hypothermia, leukocytosis and left shift of neutrophils, neutropenia, and signs of
hemodynamic compromise.[7] Peaking fever appears to be more sensitive than leukocytosis
to predict bacteremia[8]; however, fever and low-grade bacteremia can be continuous, such as
in endocarditis.
Grading the Evidence
The 2012 Surviving Sepsis Campaign Guidelines recommend obtaining appropriate cultures
before antimicrobial therapy is initiated if such cultures do not cause significant delay in
antibiotic administration.
Evidence Grade 1C: This is a strong recommendation for care based on a number of
qualitative considerations. The quality of the evidence generally derives from well-done
observational or cohort studies with controls.
References
1. W
einstein MP, Reller LP, Murphy JR, et al. The clinical significance of positive blood cultures: A comprehensive
analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations.
Reviews of Infectious Diseases. 1983;5:35–53.
2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of
severe sepsis and septic shock: 2012. Critical Care Medicine. 2013 Feb;41(2):580-637.
3. Blot F, Schmidt E, Nitenberg G, et al. Earlier positivity of central venous versus peripheral blood cultures is highly
predictive of catheter-related sepsis. Journal of Clinical Microbiology. 1998; 36:105–109.
4. Mermel LA, Maki DG. Detection of bacteremia in adults: Consequences of culturing an inadequate volume of
blood. Annals of Internal Medicine. 1993;119:270–272.
5. Bates DW, Sands K, Miller E, et al. Predicting bacteremia in patients with sepsis syndrome. Journal of Infectious
Diseases. 1997;176:1538–1551.
6. Leibovici L, Greenshtain S, Cohen O, et al. Bacteremia in febrile patients: A clinical model for diagnosis. Archives
of Internal Medicine. 1991;151:1801–1806.
7. Smith-Elekes S, Weinstein MP. Blood cultures. Infectious Disease Clinics of North America. 1993;7:221–234.
8. Groeneveld AB, Bossink AW, van Mierlo GJ, et al. Circulating inflammatory mediators in patients with fever:
Predicting bloodstream infection. Clinical and Diagnostic Laboratory Immunology. 2001;8:1189–1195.
9. Crowe M, Ispahani P, Humphreys H, et al. Bacteraemia in the adult intensive care unit of a teaching hospital
in Nottingham, UK, 1985–1996. European Journal of Clinical Microbiology and Infectious Diseases.
1998;17:377–384.
10. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through
2000. New England Journal of Medicine. 2003;348:1546–1554.
3-Hour Bundle
Content adapted extensively from:
■ Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: An evidence-based review. Critical
Care Medicine. 2004;32(11):(Suppl.)S451-S454.
■ Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of
severe sepsis and septic shock: 2012. Critical Care Medicine. 2013 Feb;41(2):580-637.
TIPS
1. C
reate a standardized protocol to manage severe sepsis that includes reminders to
draw blood cultures before administering antibiotics.
2. P
lace prompts in locations near antibiotic storage querying staff regarding whether
blood cultures have been drawn.
3. Store first dose antibiotics in automated dispensing system on unit.
3-Hour Bundle
3. A dminister Broad Spectrum Antibiotics
Related Measures
Timing of Antibiotics
Background
Once severe sepsis is identified, antibiotics must be started rapidly to treat the underlying
infection. Although early antibiotic administration seems to be an intuitive approach,
administration of effective therapies is often delayed. Evidence supports that for patients with
septic shock, the duration of hypotension prior the administration of antibiotics is a critical
determinant in the survival of septic shock.[1]
The balance of evidence unwaveringly suggests that early administration of appropriate
antibiotics reduces mortality in patients with Gram-positive and Gram-negative bacteremias.
Some of the evidence supporting early administration is based on the assumption that
patients who fail to receive appropriate antibiotics essentially represent a set of patients for
whom delay has occurred in antibiotic delivery. Several studies have confirmed the mortality
benefit associated with appropriate antimicrobials in patients with severe infections due to
Gram-negative and Gram-positive bacteria.[2-4]
In addition, the major sources of infection in severe sepsis or shock are pneumonia and intraabdominal infections [5,6] and other sources generally account for <5 percent of cases. The
prevalence of pneumonia as a cause of sepsis lends support to the case for treating severe
sepsis with early antibiotic administration. In a study of ventilator-acquired pneumonia, patients
with significant organ dysfunction (required criteria for severe sepsis) who received antibiotics
later had far greater ICU mortality: 37 percent vs. 7 percent (p=0.006); hospital mortality:
44 percent vs. 15 percent (p=0.01).[7]
Choice of Antibiotics
The choice of antibiotics should be guided by the susceptibility of likely pathogens in the
community and the hospital, as well as any specific knowledge about the patient, including
drug intolerance, underlying disease, the clinical syndrome. The regimen should cover all likely
pathogens since there is little margin for error in critically ill patients. There is ample evidence
that failure to initiate appropriate therapy promptly (i.e., therapy that is active against the
causative pathogen) has adverse consequences on outcome.[2-4]
Although restricting the use of antibiotics, and particularly broad spectrum antibiotics,
is important for limiting superinfection and for decreasing the development of antibiotic
resistant pathogens, patients with severe sepsis
or septic shock warrant broad spectrum therapy
until the causative organism and its antibiotic
susceptibilities are defined.
3-Hour Bundle
Availability
Establishing a supply of premixed antibiotics in an emergency department or critical care
unit for such urgent situations is an appropriate strategy for enhancing the likelihood that
antimicrobial agents will be infused promptly. Staff should be cognizant that some agents
require more lengthy infusion time, whereas others can be rapidly infused or even administered
as a bolus.
48- to 72-Hour Re-evaluation
Once the causative agent and antibiotic susceptibilities have been identified, restriction of
the number of antibiotics and narrowing the spectrum of antimicrobial therapy is an important
and responsible strategy for minimizing the development of resistant pathogens and for
containing costs.
The antimicrobial regimen should always be reassessed after 48 to 72 hours on the basis of
microbiological and clinical data, with the aim of using a narrow-spectrum antibiotic to prevent
the development of resistance, to reduce toxicity, and to reduce costs. Empiric combination
therapy should not be administered for more than 3 to 5 days.[12-16] Once a causative
pathogen is identified, there is no evidence that combination therapy is more effective than
monotherapy. The duration of therapy should typically be 7 to 10 days and guided by clinical
response. Longer courses may be appropriate in patients who have a slow clinical response,
undrainable foci of infection, bacteremia with S. aureus, some fungal and viral infections, or
immunologic deficiencies, including neutropenia.[17]
Dosing
All patients should receive a full loading dose of each antimicrobial. However, patients with
sepsis or septic shock often have abnormal renal or hepatic function and may have abnormal
volumes of distribution due to aggressive fluid resuscitation. The ICU pharmacist should
be consulted to ensure that serum concentrations are attained that maximize efficacy and
minimize toxicity.[8-11]
Grading the Evidence
The Grade 1 recommendations below reflect strong evidence for care based on a number of
qualitative considerations. The Grade 2 suggestions below are weaker recommendations for
care based on a number of qualitative considerations. “B” level evidence generally derives
from randomized control trials with certain limitations or very well-done observational or cohort
studies. “C” level evidence reflects well-done observational or cohort studies with controls.
“D” level evidence generally reflects case series data or expert opinion. “UG” level evidence
is ungraded.
■
■
■
dminister effective intravenous antimicrobials within the first hour of recognition of septic
A
shock (Grade 1B) and severe sepsis without septic shock (Grade 1C) as the goal of therapy.
Initial empiric anti-infective therapy of one or more drugs that have activity against all likely
pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations
into tissues presumed to be the source of sepsis (Grade 1B) should be employed.
Antimicrobial regimen should be reassessed daily for potential deescalation (Grade 1B).
3-Hour Bundle
■
■
■
■
■
■
se of low procalcitonin levels or similar biomarkers to assist the clinician in the
U
discontinuation of empiric antibiotics in patients who initially appeared septic, but have no
subsequent evidence of infection (Grade 2C).
ombination empirical therapy for neutropenic patients with severe sepsis (Grade 2B)
C
and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as
Acinetobacter and Pseudomonas spp. (Grade 2B). For patients with severe infections
associated with respiratory failure and septic shock, combination therapy with an extended
spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa
bacteremia (Grade 2B). A combination of beta-lactam and macrolide for patients with septic
shock from bacteremic Streptococcus pneumoniae infections (Grade 2B).
mpiric combination therapy should not be administered for more than 3 to 5 days.
E
De-escalation to the most appropriate single therapy should be performed as soon as
the susceptibility profile is known (Grade 2B).
uration of therapy is typically 7 to 10 days; longer courses may be appropriate in patients
D
who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus,
some fungal and viral infections, or immunologic deficiencies, including neutropenia
(Grade 2C).
ntiviral therapy initiated as early as possible in patients with severe sepsis or septic shock
A
of viral origin (Grade 2C).
ntimicrobial agents should not be used in patients with severe inflammatory states
A
determined to be of noninfectious cause (UG).
References
1. K
umar A, Roberts D, Wood KE, et al. Duration of hypotension prior to initiation of effective antimicrobial therapy
is the critical determinant of survival in human septic shock. Critical Care Medicine. 2006;34:1589-1596.
2. Leibovici L, Shraga I, Drucker M, et al. The benefit of appropriate empirical antibiotic treatment in patients with
bloodstream infection. Journal of Internal Medicine. 1998;244:379-386.
3. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital
mortality among critically ill patients. Chest. 1999;115:462-474.
4. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream
infections on patient outcomes in the ICU setting. Chest. 2000;118:146-155.
5. Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe sepsis in adults: A multicenter prospective survey in
ICUs and wards of 24 hospitals. American Journal of Respiratory and Critical Care Medicine. 1996;154:617-624.
6. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis analyzed by causative
microorganism and treatment effects of drotrecoginalfa (activated). Clinical Infectious Diseases. 2003;37:50-58.
7. Clec’h C, Timsit JF, De Lassence A. Efficacy of adequate early antibiotic therapy in ventilator-associated
pneumonia: influence of disease severity. Intensive Care Medicine. 2004;30(7):1327-1333.
8. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: A meta-analysis.
Annals of Internal Medicine. 1996;124:717-725.
9. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily
dosing of aminoglycosides. Clinical Infectious Diseases. 1997;24:796-809.
10. Amsden GW, Ballow CH, Bertino JS. Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In:
Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Fifth Edition. Philadelphia,
PA: Churchill Livingstone; 2000:253-261.
11. Hyatt JM, McKinnon PS, Zimmer GS, et al. The importance of pharmacokinetic/ pharmacodynamic surrogate
markers to outcomes. Focus on antibacterial agents. Clinical Pharmacokinetics. 1995;28:143-160.
3-Hour Bundle
12. K
umar A, Safdar N, Kethireddy S, et al. A survival benefit of combina¬tion antibiotic therapy for serious
infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/metaregression study. Critical Care Medicine. 2010;38:1651-1664.
13. Kumar A, Zarychanski R, Light B, et al. Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database
Research Group: Early combination antibiotic therapy yields improved survival compared with monotherapy in
septic shock: A propensity-matched analysis. Critical Care Medicine. 2010;38:1773-1785.
14. Micek ST, Welch EC, Khan J, et al. Empiric combination antibiotic therapy is associated with improved outcome
against sepsis due to Gram-negative bacteria: A retrospective analysis. Antimicrob Agents Chemother.
2010;54:1742-1748.
15. Al-Hasan MN, Wilson JW, Lahr BD, et al. Beta-lactam and fluoroquinolone combination antibiotic therapy for
bacteremia caused by gram-negative bacilli. Antimicrob Agents Chemother. 2009;53:1386-1394.
16. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis.
2004;39(Suppl1):S32-S37.
17. Hotchkiss RS, Opal S. Immunotherapy for sepsis: A new approach against an ancient foe. New England Journal
of Medicine. 2010;363:87-89.
Content adapted extensively from:
■ Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of
severe sepsis and septic shock: 2012. Critical Care Medicine. 2013 Feb;41(2):580-637.
■ Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock:
An evidence-based review. Critical Care Medicine. 2004;32(Suppl):S495-S512.
TIPS
1. E
stablish a standardized clinical protocol that includes the empiric administration of
antibiotics in severe sepsis within 1 hour of presentation.
2. E
stablish a pre-mixed quantity of broad spectrum antibiotics available in the emergency
department and ICU, in order to avoid delays involving pharmacy acquisition of the
antibiotic.
3. Infuse antibiotics through multiple lines as available in order to speed delivery of agents.
4. Cover both Gram-positive and Gram-negative organisms.
5. C
onsider specific knowledge about the patient’s past organism burden, if available
(including fungal infection); the setting from which the patient arrived in the emergency
department (e.g., another institution that may harbor resistant organism); and
community and hospital resistance patterns in making choices.
3-Hour Bundle
4. A
dminister 30 mL/kg Crystalloid
for Hypotension or Lactate ≥4 mmol/L
In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or
lactate ≥4 mmol/L (36 mg/dL):
■
Measure central venous pressure (CVP)*
■
Measure central venous oxygen saturation (ScvO2)*
*Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg, ScvO2
of ≥70 percent, and lactate normalization.
Background
Patients with severe sepsis and septic shock may experience ineffective arterial circulation
due to the vasodilatation associated with infection or impaired cardiac output. Poorly perfused
tissue beds result in global tissue hypoxia, which is often found in association with an elevated
serum lactate level. A serum lactate value greater than 4 mmol/L (36 mg/dL) is correlated
with increased severity of illness and poorer outcomes even if hypotension is not yet present.
As such, patients who are hypotensive or have a lactate greater than 4 mmol/L (36 mg/dL)
require intravenous fluids to expand their circulating volume and effectively restore
perfusion pressure.
Initial Fluid Administration
The Severe Sepsis 3-Hour Resuscitation Bundle calls for an initial administration of 30 mL/kg
of crystalloid as a fluid challenge in cases of suspected hypovolemia or actual cases of serum
lactate greater than 4 mmol/L (36 mg/dL).
Fluid resuscitation should be commenced as early as possible in the course of septic shock
(even before intensive care unit admission). Requirements for fluid infusion are not easily
determined so that repeated fluid challenges should be performed.
The targets for quantitative resuscitation provided in the guidelines are CVP of ≥8 mm Hg,
ScvO2 of ≥70 percent, and normalization of lactate.
3-Hour Bundle
Fluid Challenge vs. Increase in Maintenance Fluids
An increase in maintenance fluid administration must be distinguished from fluid challenge.
Fluid challenge is a term used to describe the initial volume expansion period in which the
response of the patient to fluid administration is carefully evaluated. During this process, large
amounts of fluids may be administered over a short period of time under close monitoring to
evaluate the patient’s response.
Fluid challenges require the definition of four components: 1) the type of fluid to be
administered; 2) the rate of fluid infusion (e.g., 500 mL to 1,000 mL over 30 minutes); 3) the
end points (e.g., mean arterial pressure of >65 mm Hg, heart rate of <110 beats per minute);
and 4) the safety limits (e.g., development of pulmonary edema). Maintenance fluid increases
typically alter only the rate of administration of continuous fluids.
Crystalloid vs. Colloid
Although prospective studies of choice of fluid resuscitation in patients with septic shock only
are lacking, a prospective, controlled, randomized, double-blind study comparing 4 percent
human albumin solution with 0.9 percent sodium chloride (saline) in critically ill patients
requiring fluid resuscitation (SAFE study) has been completed. The results of this study
showed identical mortality rates in patients receiving albumin or 0.9 percent sodium chloride.
Subgroup analysis revealed that albumin might have some (albeit not statistically significant)
benefit in patients with severe sepsis.[1]
In addition, meta-analyses of clinical studies comparing crystalloid and colloid resuscitation
in general and surgical patient populations indicate no clinical outcome difference between
colloids and crystalloids and would appear to be generalizable to sepsis populations.[2-4] As
the volume of distribution is much larger for crystalloids than for colloids, resuscitation with
crystalloids requires more fluid to achieve the same goals and results in more edema.
End Points of Fluid Resuscitation
For the Severe Sepsis 3-Hour Resuscitation Bundle, a minimum fluid challenge is defined in
an effort to avoid hypotension. The bundle does not restrict additional fluids. If, however, the
patient should enter the early goal-directed phases of the 6-Hour Septic Shock Bundle, either
for hypotension not responding to fluid challenges or a lactate ≥4 mmol/L (36 mg/dL), targets
for central venous pressure as well as central and mixed venous oxygen saturation have been
defined. These targets are not arbitrary. They are based on specifications defined in the best
available literature[5], and a recent analysis supporting a 65 percent SvO2 saturation as similar
to a 70 percent ScvO2.[6]
In Rivers et al., hospital mortality was 30.5 percent in the group assigned to early goaldirected therapy, compared with 46.5 percent in the standard therapy group (p=0.009).[5]
Rivers et al. used restoration of a central venous oxygen saturation of >70 percent as one of
their goals, and this was met in 95 percent of the early goal-directed group, compared with
just 60 percent of the standard treatment group (p<0.001). Patients in the early goal-directed
treatment groups received more fluids (5 vs. 3.5 L, p<0.001) and more were given red cell
transfusions (64 vs. 18.5 percent, p<0.001) in the first 6 hours than in the standard treatment
group, emphasizing the importance of early and adequate fluid resuscitation in patients with
severe sepsis.
3-Hour Bundle
However, considerable debate remains on these thresholds largely because of problems in
monitoring the regional microcirculation and oxygenation. Changes may persist at a local
level while systemic hemodynamic and oxygenation variables seem to have stabilized. Each
end point must be considered in its context, and the combination of clinical variables (mean
arterial pressure, urine output, apparent skin perfusion, level of consciousness) along with
serum lactate values may be helpful to the clinician despite a lack of randomized trials to
establish this point.
Safety Margins
Patients should be carefully observed for evidence of pulmonary and systemic edema
during fluid resuscitation. The degree of intravascular volume deficit in patients with severe
sepsis varies. With venodilation and ongoing capillary leak, most patients require continuing
aggressive fluid resuscitation during the first 24 hours of management. Input is typically much
greater than output, and input/output ratio is of no utility to judge fluid resuscitation needs
during this time.
Grading the Evidence
The Grade 1 recommendations below are based on strong evidence for care based on a
number of qualitative considerations. “B” level evidence generally derives from randomized
control trials with certain limitations or very well-done observational or cohort studies. “C”
level evidence reflects well-done observational or cohort studies with controls. “D” level
evidence generally reflects downgraded controlled studies or expert opinion based on other
evidence. “UG” level evidence is ungraded.
■
■
■
The 2012 Surviving Sepsis Campaign Guidelines recommend fluid resuscitation with
crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic
shock (Grade 1B). The absence of any clear benefit following the administration of colloid
solutions compared to crystalloid solutions, together with the expense associated with
colloid solutions, supports a high-grade recommendation for the use of crystalloid solutions
in the initial resuscitation of patients with severe sepsis and septic shock.
he Surviving Sepsis Campaign recommends fluid resuscitation initially target a CVP of at
T
least 8 mm Hg (12 mm Hg in mechanically ventilated patients). Further fluid therapy is often
required (Grade 1C).
he Surviving Sepsis Campaign recommends that a fluid challenge technique be applied,
T
wherein fluid administration is continued as long as the hemodynamic improvement (e.g.,
arterial pressure, heart rate, urine output) continues (UG). The Surviving Sepsis Campaign
recommends fluid challenge in patients with suspected hypovolemia be started with at
least 30 mL/kg of crystalloids (a portion of this may be albumin equivalent) over 30
minutes. More rapid administration and greater amounts of fluid may be needed in patients
with sepsis-induced tissue hypoperfusion (Grade 1C). The Surviving Sepsis Campaign
recommends the rate of fluid administration be reduced substantially when cardiac filling
pressures (CVP or pulmonary artery balloon-occluded pressure) increase without concurrent
hemodynamic improvement (Grade 1D).
3-Hour Bundle
References
1. F infer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive
care unit. New England Journal of Medicine. 2004;350:2247-2256.
2. Choi PTL, Yip G, Quinonez LG, et al. Crystalloids vs. colloids in fluid resuscitation: A systematic review. Critical
Care Medicine. 1999;27:200-210.
3. Cook D, Guyatt G. Colloid use for fluid resuscitation: Evidence and spin. Annals of Internal Medicine.
2001;135:205-208.
4. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients:
A systematic review of randomized trials. British Medical Journal. 1998;316:961-964.
5. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic
shock. New England Journal of Medicine. 2001;345:1368-1377.
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Content adapted extensively from:
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management
of severe sepsis and septic shock: 2012. Critical Care Medicine. 2013 Feb;41(2):580-637.
■ Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: An evidence-based review. Critical
Care Medicine. 2004;32(Suppl):S451-S454.
■ Rhodes A, Bennett ED. Early goal-directed therapy: An evidence-based review. Critical Care Medicine.
2004;32(Suppl):S448-S450.
■